WO2010063802A1 - Cyclobutène-1,2-diones 3,4-disubstituées en tant qu'antagonistes de récepteur cxcr2 - Google Patents

Cyclobutène-1,2-diones 3,4-disubstituées en tant qu'antagonistes de récepteur cxcr2 Download PDF

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WO2010063802A1
WO2010063802A1 PCT/EP2009/066354 EP2009066354W WO2010063802A1 WO 2010063802 A1 WO2010063802 A1 WO 2010063802A1 EP 2009066354 W EP2009066354 W EP 2009066354W WO 2010063802 A1 WO2010063802 A1 WO 2010063802A1
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hydroxy
dioxo
cyclobut
optionally substituted
furan
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PCT/EP2009/066354
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English (en)
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Urs Baettig
Ian Bruce
Neil John Press
Simon James Watson
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms

Definitions

  • the present invention relates co organic compounds, e.g. compounds of formula (I), and to uses thereof.
  • the present invention provides a compound of formula I ) or solvates, hydrates or pharmaceutically acceptable salts thereof, wherein
  • R 1 is H or Ci-Cs alkyl, wherein the alkyl group is optionally substituted by one or more halogen atoms;
  • R 2 is a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups or a 3 fo 10 membered heterocyclic group optionally substituted by one or more Z groups;
  • R J and R 2 together with the carbon arom to which they are attached form a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups or a 3 to 10 membered heterocyclic group including one or more heteroatoms independently selected from N, O and
  • Ar is phenyl, naphthyl or benzotriazolyl; optionally substituted by one, two or three R' groups; each R 3 is independently selected from OH, halogen, cyano, C) -Q alkyl, CO2H, CChCr
  • R 4 is H, Ci-Cs alkyl, Ci-Cs cycloaikyl, Cs-O cycloalkertyj or (Ci-Q alkylJ-R 6 , wherein the alkyl groups are each optionally substituted by one or more halogen atoms;
  • R s is Ci-O alkyl, CrQ alkyl-O CVCg aikyl, C 1 -Cs alkyl O-Ph, Cj-Cw cycloaikyl, Cs-Ci 0 cvcloalkenyl, a 3 to 10 membered heterocyclic group, (Cj-O aikyl)-Os-Cio cycloaikyl or (C1-C4 alkyl ⁇ -Cj-C ⁇ o cycloaikenyl, wherein the aikyl groups and ring systems are each optionally substituted by one or more halogen atoms, OH or CFj groups; or R 4 and K s t together with the nitrogen atom to which they are attached, form a 5 to 10 membered heterocyclic group optionally containing one or more additional heteroatoms and optionally substituted by one or more Z groups, provided that the heterocyclic ring does not include an oxygen atom adjacent to the sulfonamide
  • R 6 is selected from a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more
  • R 7 and R s are each independently selected from H, Ct-Cs alkyl, C3-C.0 cycloalkyl, Cs-Cio cycloalkenyl and -(Ci-Ca alkyleneJ-Cs-Cio cycloalkyl;
  • R' is selected from H, Ci-Gs alkyl, -(Ct-C? alkylene)-CvCio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the alkyl groups and ring systems is optionally substituted by OH, halo, C1-C3 alkyl and Ci-Q alkoxy;
  • Z is independently selected from OH, a 3 to 10 membered carbocyclic group, a 3 to 10 membered heterocyclic group, benzyl, Q-Q alkyl optionally substituted by one or more halogen atoms or OH groups, Q-O alkox7 optionally substituted by one or more halogen atoms or OH groups, -O-aryl, -O-aralkyl, -0(CH 2 ) ⁇ C(O)E, NR ⁇ (SO 2 )R 1 *, (SO 2 )NR W R i S
  • E is NR O R 12 Or OR 12 ; each R U) and R" are independently selected from H, Ci-Q alky!, O-Cjo cycloalkyl, CVCio cycloalkenyl and -(Ci-Cj alkyleneJ-Cj-Cio cycloalkyl; and each R t * is selected from H, Ci -C « alkyl, -(Ci Cjs alkylene) Cv-Cio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the ring systems is optionally substituted by OH, halo, CrCj alkyl and Ci-Q alkoxy, provided that when Ar is phenyl which is bonded to the amine nitrogen in the 1 -position, is substituted by OH at the 2-po.sition and is further substituted at the 3-position, then R 2 is not a 5-membered non-aromatic carb
  • R 1 is H or Ci-O alkyl, suitably methyl or ethyl, especially ethyl, and the other variables are as defined anywhere herein.
  • R z is a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; and the other variables are as defined anywhere herein.
  • R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; and the other variables are as defined anywhere herein.
  • R 1 is H or CV C4 alfcyl
  • R 2 is a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups
  • R f and R 2 together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups.
  • R 2 is a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably an oxygen-containing heterocyclic group, such as a furanyl or tetrahydrofuranyl group, more suitably a furanyl group, optionally substituted by one or more Z groups, suitably a Ci-Q alkyl group, such as a methyl group; and the other variables are as defined anywhere herein.
  • K ⁇ is a 4 to 6 membered carbocyclic group, suitably a phenyl group, optionally substituted by one or more Z groups, suitably halogen such as fluorine, or a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably a nitrogen or an oxygen-containing heterocyclic group, such as a piperidtnyl, pyranyl, furanyl or tetrahydrofuranyl group, more suitably a furanyl group, optionally substituted by one or more Z groups, suitably a Ci-C» alkyl group, such as a methyl group; and the other variables are as defined anywhere herein.
  • R 1 and R 2 together with the carbon atom to which they are attached form a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably a sulfur-containing heterocyclic group, such as a terrahydrothiophenyl group, optionally substituted by one or more Z groups, suitably an unsubstituted tetrahydrothiophenyl group; and the other variables are as defined anywhere herein.
  • R 2 is furanyl substituted by methyl.
  • Ar is phenyl, naphthyl or benzotriazoiyl; optionally substituted by one or two R 3 groups; and the other variables are as defined anywhere herein.
  • Ar is phenyl; optionally substituted by one or two R 3 groups; and the other variables are as defined anywhere herein.
  • the phenyl group is substituted by one or two R 3 groups; and the other variables are as defined anywhere herein.
  • the phenyl group when p is 1 and Ar is phenyl, the phenyl group is substituted in the ortho- position by OH and in the meta- position by the sulfonamide substituent; and the other variables are as defined anywhere herein.
  • the phenyl group when p is 1 and Ar is phenyl, the phenyl group is substituted in the ortho- position by OH, in the meta- position by the sulfonamide substituent and in the para- position by R 3 , suitably chlorine; and the other variables are as defined anywhere herein.
  • R 3 is OH, halogen, suitably fluorine or chlorine, Ci- C 4 alkyl, CO 2 OH, COiO-Oalkyl, C(0)N(Ci-Oalkylh, CH(OH)(CF 3 )I, NO 2 , tetrazolyl, and C(O)Ph substituted by halogen, suitably chlorine; and the other variables are as defined anywhere herein.
  • R 4 is H, Ct-O alkyl, C3-O cycloalkyl or (Ci-Q alkyty-Cv-O cycloalkyl, more suitably R* is H or CVQ alkyl; and the other variables are as defined anywhere herein.
  • R 5 is Ci-O alkyl, Ci-Ce alkyl (O) Cj-Q alkyl, Ci-Cg alkyl (O)Ph, C3-C10 cycloalkyl, O-Cto cycloalkenyl, including phenyl, a 3 to 10 membered heterocyclic group, wherein the alkyl groups and ring systems are each optionally substituted by one or more OH or CF3 groups; and the other variables are as defined anywhere herein.
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic group, optionally containing one or more additional heteroatoms, suitably a nitrogen atom, and optionally substituted by one or more Z groups, suitably OH or a 3 10 10 membered carbocyclic group, more suitably OH or a 5 membered carbocyclic group; and the other variables are as defined anywhere herein.
  • Z is selected from Ci-O alkyl, OH, halogen such as fluorine, or a 3 to 10 membered carbocyclic group; and the other variables are all as defined anywhere herein.
  • the present invention provides a compound of formula ( ⁇ ) selected from:
  • Alkyl includes linear or branched Ci-Cs alkyl, such as Ci-Cs alkyl or Ci-O alkyl, e.g. Cj- Cz alkyl, including uns ⁇ bstituted or substituted alkyi, e.g. alkyl substituted by groups which are conventional in organic chemistry, e.g. halogen, OH, NH ⁇ or haio ⁇ Cu)aikyl,
  • Halogen includes fluoro, chloro, bromo, iodo, e.g. fluoro, chloro, bromo, suitably chloro,
  • Carbocyclic group denotes a ring system consisting of the relevant number of carbon atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10.
  • the ring system may be a single ring, a fused ring system or a spirocyclic ring system.
  • the carbocyclic group may be saturated, partially unsaturated or aromatic. In particular, it may include a saturated or partially unsaturated ring fused to an aromatic ring or a second saturared or partially unsaturated ring; or it may include two aromatic rings fused together.
  • “carbocyclic group” includes, for example, cycloalkenyl, cycloalkyl, phenyl, indane, indene, naphthalene, tetralin and azulene.
  • Heterocyclic group denotes a ring system consisting of the relevant number of member atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10, including at least one heteroatom selected from N 5 O and S.
  • the ring system may be a single ring, a fused ring system or a spirocyclic ring system.
  • the heterocyclic group may be saturated, partially unsaturated or aromatic (i.e. heterocyclic includes heterocycloalkyl, heterocycloalkenyl and heteroaryl). In particular, it may include a saturated or partially unsaturated ring fused to an aromatic ring or a second saturated or partially unsaturated ring; or it may include two aromatic rings fused together.
  • the heterocyclic group includes a heterocyclic ring fused to a cnrbocyclic ring, e.g. benzofused heterocyclic groups.
  • the heterocyclic group includes 1, 2 or 3 heteroatoms selected from N, C ) and S.
  • compositions of formula ⁇ that contain a basic centre are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, caprylic acid, dichloroacetic acid, hippuric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, gluconic acid, mandelic acid, dicarboxylic acids such as maleic acid or succinic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, malonic acid, sebacic acid, aromatic carboxylic acids such as
  • Compounds of formula I which contain acidic, e.g. carboxyl, groups are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine, arginine, benethamme, benzathine, dierhanolamine, 4- ⁇ 2-hydro ⁇ y «ethyl)mor ⁇ holme, 1 -(2-hydroxyethy l)pyrrolidine, N-meihyl glutamine, piperazine, methanol-amine, choline or tromethamine.
  • suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic
  • solvates in accordance with the invention include those wherein the solvent of crystallisation may be isotopkally substituted e.g. DzO, d ⁇ acerone or d$- DMSO.
  • Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation.
  • Compounds of formula I can be recovered from reaction mixtures and purified i ⁇ a conventional manner.
  • Isomers, such as e ⁇ antiomers may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • Some compounds of the invention contain at least one asymmetric carbon atom and thus they exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic mixtures. In cases where additional asymmetric centres exist the present invention also embraces both individual optically active isomers as well as mixtures, e.g. diostereomerk mixtures, thereof.
  • the invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or; by stereospecific or asymmetric syntheses.
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least .98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
  • the invention includes all pharmaceutically acceptable isotopicaily-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention inducfe isotopes of hydrogen e.g. 2 H and 3 H, carbon e.g. 11 C, 13 C and 14 C, chlorine e.g. 36 Cl, fluorine e.g. 18 F, iodine e.g. m l and 125 I, nitrogen e.g. 1J N and ! S N, oxygen e.g. 15 0, 17 O and ⁇ O, and sulfur e.g. 3S S.
  • Certain isotopicaily-labelled compounds of formula I are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium ( ⁇ H) and carbon- 14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium ( 1 H) may afford certain therapeutic advantages that result from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, U O, and n N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy,
  • PET Positron Emission Topography
  • Isotopicaily-labelled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used.
  • Some of the compounds of Formula I may exist in different tautomeric forms. Tautomerism is well known to those skilled in the art and the skilled person will readily appreciate which groups are able to tautomerise to form the different tautomeric forms.
  • the invention includes all tautomeric forms of the compounds of Formula I.
  • Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein.
  • Starting materials are known or may be prepared according, e.g. analogously, to a method as conventional or as described herein.
  • a compound of formula I thus obtained may be converted into another compound of formula I, e.g. or a compound of formula I obtained in free form may be converted into a salt of a compound of formula ⁇ and vice versa.
  • Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein.
  • Starting materials are known or may be prepared according, e.g. analogously, to a method as conventional or as described herein.
  • the present invention provides a process for the preparation of a compound of the present invention comprising:
  • the present invention provides a process for the preparation of a compound of the present invention comprising:
  • the present invention provides a process for the preparation of a compound of the present invention comprising:
  • Vl with a compound of formula (III) wherein R 1 and R 2 together with the carbon arom to which they are attached form a 3 to 10 membered carbocyciic group optionally substituted by one or more Z groups or a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, and a compound of formula (V) wherein Ar, p, R 4 and R 5 are as defined above, under appropriate conditions, e.g. in the presence of triethylamine, ethanol, for an appropriate time, e.g. 2 to 24 hours, at appropriate temperatures, e.g. room temperature, to obtain a compound of formula (I) of the invention.
  • a compound of formula ⁇ thus obtained may be converted into another compound of formula I, e.g. or a compound of formula I obtained in free form may be converted into a salt of a compound of formula I and vice versa.
  • the invention also provides a compound of formula I in free or phsirmaceuticaiiy acceptable salt form for use as a pharmaceutical.
  • the present invention provides the use of a compound of fo ⁇ nula(I) wherein the substituenrs are as defined above as a pharmaceutical.
  • the compounds of the invention act as CXCR2 receptor antagonists, thereby inhibiting the infiltration and activation of inflammatory cells, in particular neutrophils, monocytes and CD8+ T cells and mediators involved in chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention therefore provide symptomatic relief and reduce disease progression.
  • the airways of subject with COPD exhibit an inflammatory response which is predominantly neutrophilic.
  • CD8+ T cells and epithelial ceils are activated and release pro-inflammatory mediators, oxidants, cytokines and neutophilic chemotactic factors .
  • IL-8, GRO ⁇ , ENA-78 and teuk ⁇ trienes. 11,-8, GRO ⁇ and ENA-78 are selective chemoattractants for neutrophils.
  • IL-8 binds two distinct receptors with similar affinity, CXCRl and CXCR2. Closely related chemokines including GRO ⁇ , ⁇ , y, NAP-2 and ENA-78 bind only to CXCR2.
  • Inhibiting neutrophil recruitment is therefore a recognised therapeutic strategy for treating several lung diseases.
  • Blocking the binding of IL-8, GRO ⁇ and ENA-78 to the che ⁇ iokine receptor CXCR2 can provide beneficial effects in patients with COPD by suppressing the infiltration and activation of key inflammatory cells, thereby reducing subsequent tissue damage, mucus secretion, airflow obstruction and disease progression.
  • IL-8 and GROtt chemoki ⁇ e inhibitory properties of compounds of the invention can be demonstrated in the following assays:
  • [ 125 I] IL-8 ⁇ human recombinant are obtained from Amersham Pharmacia Biotech, with specific activity 2000 Ci/mmol. All other chemicals are of analytical grade.
  • Human recombinant CXCR2 receptor expressed in Chinese hamster ovary cells (CHO-Kl) is purchased from Euroscreen, The Chinese hamster ovary membranes are prepared according to protocol supplied by Euroscreen. Membrane protein concentration is determined using a Bio- Rad protein assay. Assays are performed in a 96-weli micro plate fo ⁇ nat according the method described in White, et al., J Biol Chem., 19.98, 273, 10095).
  • Each reaction mixture contains 0.05 mg/rnl CXCR2 membrane protein in 20 mM Bis-Tris-propane, pH 8.0, containing 1.2 mM MgSO 4 , 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
  • compound of interest pre-dissolved in dimerhylsulphoxide (DMSO) so as to reach a final concentration of between 10 ⁇ M and 0.0005 ⁇ M (final concentration of DMSO 2 % (v/v)) is added. Binding is initiated by addition of 0.02 iiM 125 I-IL-S.
  • DMSO dimerhylsulphoxide
  • the plate is harvested using a BrandellTM 96-weli harvester onro glass fibre filter plate (GF/c) blocked with 1% polyethyleneimine + 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCI, 1 mM MgSO 4 , OJ mM EDTA, 0.03% CHAPS, pH 7.4. The filter is dried at 5O 0 C overnight. Backseal is applied to the plate and 50 ⁇ l of liquid scintillation fluid added. The counts are measured on the Packard Topcount ' ⁇ M scintillation counter.
  • GF/c BrandellTM 96-weli harvester onro glass fibre filter plate
  • P 5 Sj-GTIY? binding assay for human CXCR2 receptor using SPA technology [ 35 Sj-GTTyS (with .specific activity 1082 Ci/mmol) and wheat germ agglutinin poly vinyl toluene scintillation proximity beads are purchased from Amershaxn Pharmacia Biotech.
  • the Chinese hamster ovary cell (CHO-Kl) membranes expressing human CXCR2 receptors are purchased from Biosignal Packard Inc. All other chemicals are of analytical grade.
  • White non- binding surface 96 well OptiplateTM microplates are obtained from Packard.
  • Recombinant human IL-8 is synthesised, cloned and expressed in Escherichia coli as described previously (Lindiey I, et al., Proc. Nad. Acad. ScL, 1988, 85 ⁇ 23):9199).
  • the assay is performed in duplicate in 96 well OptiplateTM microplate in a final volume of 250 ⁇ l per well.
  • Compounds are diluted in DMSO (0.5% final concentration) and incubated in 20 ⁇ iM FIEPES buffer pH 7.4 containing 10 mM MgQ 2 , 100 mM NaCI, 1 mM EDTA plus 100 nM IL-8, 50 ⁇ M GDP and 500 pM FS ⁇ GTP ⁇ S per well.
  • SPA beads (1 mg/well final concentration) were pre-mixed with the membranes (10 ⁇ g/well final concentration) in assay buffer: 20 mM HEPES buffer pH 7.4 containing 10 mM MgO 2 , 100 mM NaCI, 1 mM EDTA.
  • the bead membrane mixture is added to each well, plates are sealed and incubated at room temperature for 60 minutes. The plate is centrifuged and read on Packard TopCount T1 * scintillation counter, program [ 3S S dpm j for 1 ⁇ n/well. Data are expressed as the % response to 100 nM IL-8 minus basal.
  • the in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay. Assays are performed in a 96- well plate format according to previously published method (Frevert C W, et al., J Immunology Methods, 1998, 213, 41 ). 96-well chemotaxis chambers 5 ⁇ m are obtained from Neuro Probe, all cell buffers are obtained from Invitrogen Paisley, UK, dextran -T500 and Ficoll-Paque PlusTM density gradient centrifugation media are purchased from Pharmacia Biotech Buckinghamshire, UK. Calcein-AM dye is obtained from Molecular Probes. Neutrophils are isolated as previously described (Hasiett, C, et al. Am) Path., 1985, 1.19:101).
  • Isolated neutrophils (1 xlO 7 ) are labelled with the ffuorochrome calcein-AM (5 ⁇ g) in a total volume of 1 ml and incubated for 30 minuses at 37 0 C.
  • the labelled cells are washed with RPMI without phenol red + 0.1 % bovine serum albumin, prior co use the cells are counted and adjusted to a final concentration of 5 x 10* cells /ml.
  • the labelled neutrophils are then mixed with test compounds (0.001-1000 nM) diluted in DMSO (0.1 % final concentration) and incubated for 10 minutes at room temperature.
  • the chemoattractants (29 ⁇ l) are placed in the bottom chamber of a 96-well chemotaxis chamber at a concentration between (0.1-5 nM).
  • the polycarbonate filter (5 ⁇ m) is overlaid on the plate, and the cells (25 ⁇ l) are loaded on the top filter.
  • the cells are allowed to migrate for 90 minutes at 37° C in a humidified incubator with 5% CCb..
  • migrated cells are quantified using a multi-well fluorescent plate reader (Fluroskan 11TM, labsystems) at 485 nm excitation and 538 nm emission. Each compound is tested in quadruplet using 4 different donors. Positive control cells, i.e.
  • Negative control cells i.e. those that have not been stimulated by a chemoattractant, are added to the bottom chamber. The difference between the positive control and negative control represents the chemotactic activity of the cells.
  • the compounds of the Examples herein below have ICso values below 10 ⁇ M in the [ 3S S] ⁇ GPTyS binding assay.
  • Table A provides the iC.to values for a selection of compounds.
  • compounds of the invention are useful in the treatment of conditions or diseases mediated by CXCR2, for example inflammatory or allergic conditions or diseases, particularly chronic obstructive pulmonary airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, bronchiolitis obliterans syndrome and severe asthma.
  • COPD chronic obstructive pulmonary airways or lung disease
  • COAD chronic obstructive pulmonary airways or lung disease
  • Compounds of the present invention are further useful in the treatment of various diseases, such as cancer, e.g. ovarian cancer, prostate cancer, melanoma including metastatic melanoma, lung cancer, e.g.
  • non small cell lung cancer renal cell carcinoma
  • tumour angiogenesis ischae ⁇ a/reperfusion injury, delayed graft function, osteoarthritis, myeloid metaplasia with myelofibrosis, ⁇ detiomyosis, contact hypersensitivity (skin), and in wound healing.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • Prophylactic efficacy in the treatment of chronic bronchitis or COPD will be evidenced by reduced frequency or severity, will provide symptomatic relief and reduce disease progression, improvement in lung function. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • symptomatic therapy i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • inflammatory or obstructive airways diseases and conditions to which the invention is applicable include acute lung injury (ALI), acure/adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, fibroid I ting, airway hyperresponsiveness, dyspnea, pulmonary fibrosis, allergic airway inflammation, small airway disease, lung carcinoma, acute chest syndrome in patients with sickle cell disease and pulmonary hypertension, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ALI acute lung injury
  • ARDS acure/adult respiratory distress syndrome
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • inflammatory or obstructive airways diseases to which the invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tahacosis and byssinosis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracos
  • Compounds of the invention are also useful for treating respiratory viral infections, which exacerbate underlying chronic conditions such as asthma, chronic bronchitis, COPD, otitis media, and sinusitis.
  • the respiratory viral infection treated may be associated with secondary bacterial infection, such as otitis media, sinusitis or pneumonia.
  • Compounds of the invention are also useful in the treatrnent of inflammatory conditions of the skin, for example psoriasis, atopic dermatitis, lupus erythematosus, and other inflammatory or allergic conditions of the skin.
  • Compounds of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, diseases affecting the nose including allergic rhinitis, e.g. atrophic, chronic, or seasonal rhinitis, inflammatory conditions of the gastrointestinal tract, for example inflammatory bowel disease such as ulcerative colitis and Crohn's disease, diseases of the bone and joints including rheumatoid arthritis, psoriatic arthritis, and other diseases such as atherosclerosis, multiple sclerosis, and acute and chronic allograft rejection, e.g. following transplantation of heart, kidney, liver, lung or bone marrow.
  • diseases or conditions having an inflammatory component for example, diseases affecting the nose including allergic rhinitis, e.g. atrophic, chronic, or seasonal rhinitis, inflammatory conditions of the gastrointestinal tract, for example inflammatory bowel disease such as ulcerative colitis and Crohn's disease, diseases of the bone and joints including rheumato
  • Compounds of the invention are also useful in the treatment of endotoxic shock, glomerulonephritis, cerebral and cardiac ischemia, Alzheimer's disease, cystic fibrosis, virus infections and the exacerbations associated with them, acquired immune deficiency syndrome (AIDS), multiple sclerosis (MS), Helicobacter pylori associated gastritis, and cancers, particularly the growth of ovarian cancer.
  • AIDS acquired immune deficiency syndrome
  • MS multiple sclerosis
  • Helicobacter pylori associated gastritis and cancers, particularly the growth of ovarian cancer.
  • Compounds of the invention are also useful for treating symptoms caused by viral infection in a human which is caused by die human rhinovirus, other enterovirus, coronavirus, herpes viruses, influenza virus, parainfluenza virus, respiratory syncytial virus or an adenovirus. Compounds of the invention are also useful for treating pancreatitis .
  • a compound of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. mouse, rat or rabbit model, of airway inflammation or other inflammatory conditions, for example as described by Wada et al,/. Exp. Med (1994) 180:1135-40; Sekido et al, Nature (1993) 365:654-57; Modelska et al., Am, ]. Respir. Crit. Care. Med (1999) 160r 1450-56; and Laffon et al (1999) Aw. /. Re ⁇ ir. Crit Care Med. 160:1443-49.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with rhe other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular giucocorticosteroids such as budesonide, beclamethaso ⁇ e dipropionate, fluticasone propionate, cidesonkk' or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11., 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO
  • Suitable bronch ⁇ diiatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, US 3714357, US 5171744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO 04/05285, WO2004096800, WO2006048225 and WO200802554 ⁇ ; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salrneterol fenorerol, procaterol, and especially, forrnoterot, carmoterol and pharmaceutically acceptable salts thereof, and compounds (
  • antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarare, promethazine, loratidine, desloraridine, diphenhydramine and fexofenadine hydrochloride.
  • Combinations of compounds of the invention and anticholinergic or antimuscarinic compounds, steroids, beta-2 agonist*;, PDE4 inhibitors, dopamine receptor agonists, LTD4 antagonists or LTB4 antagonists may also be used.
  • Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with other antagonists of chemokin ⁇ receptors, e.g.
  • TAK-770 N-([4- ⁇ (6,7-di
  • the invention also provides a method for the treatment of a condition or disease mediated by CXCR2, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof an effective amount of a compound of formula 1 in a free or pharmaceutically acceptable salt form as hereinbefore described.
  • the invention provides the use of a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for the manufacture of a medicament for the treatment of a condition or disease mediated by CXCR2, for example an inflammatory or allergic condition or disease, particularly an inflammatory or obstructive airways disease.
  • the invention provides a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for the treatment of a condition or disease mediated by CX CR2, for example an inflammatory or allergic condition or disease, particularly an inflammatory or obstructive airways disease.
  • the compounds of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of formula ⁇ in free or pharmaceutically acceptable salt form, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • the composition may contain a eo-therapeutic compound such as an anti-inflammatory bronchodilarory or antihistamine drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFAl 34a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanoi (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose.
  • HFA hydro-fluoro-alkane
  • ethanoi up to 20% by weight
  • surfactants such as oleic acid or sorbitan trioleate
  • bulking agents such as lactose
  • the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula I having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g. magnesium stearare.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation
  • it preferably contains, for example, the compound of formula i either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.
  • the invention includes (A) a compound of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, (B) an inhalable medicament comprising a compound of the invention in inhalable form; (C) a pharmaceutical product comprising such a compound of the invention in inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of the invention in inhalable form.
  • A a compound of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form
  • B an inhalable medicament comprising a compound of the invention in inhalable form
  • C a pharmaceutical product comprising such a compound of the invention in inhalable form in association with an inhalation device
  • an inhalation device containing a compound of the invention in inhalable form.
  • Dosages of compounds of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.01 to 1 mg/kg per clay while for oral administration suitable daily doses are of the order of 0.005 to JOO mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the invention is illustrated by die following Examples.
  • Especially preferred compounds of the present invention include compoundsS of formula I
  • Mass spectra were run on LCMS systems using electrospray ionization. These were either Agilent 1100 ⁇ lPLQMicrornass Platform Mass Spectrometer combinations or Waters Acquity UPLC with SQD Mass Spectrometer. ⁇ M+HJ + refers to mono-isotopic molecular weights.
  • NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometers using ⁇ CO N-NMR. Spectra were measured at 298 K and were referenced using the solvent peak.
  • the various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.
  • Such reagents and materials include: IsoluteTM (available from Biotage), HyfloTM, CeiiteTM and can be readily obtained from the suppliers indicated.
  • This compound was prepared by an analogous procedure to Example 4 by replacing 3- aminophenol hydrochloride with 2-(2-aminophenyl)-l,l ,l,3,3,3-hexafluoropropan-2-oL
  • the tide compound was prepared by an analogous procedure to Example 6 by replacing 3- ethoxy-4-(2-hydroxy-4-m €thy!-phenyiamino)-cyc!obut-3-ene-l,2-dione with Intermediate CD. (M + H]* 319.
  • the reaction mixture was stirred ar room temperature for 48 h.
  • the reaction mixture was partitioned between EtOAc (50 ml) and IM HCl (20 ml) and the organic layer was separated, dried (MgS ⁇ 4) and filtered.
  • Silica gel (2 g) was added to the filtrate and evaporated to dryness in vacuo.
  • the compound was dry- loaded onto a silica column (12 g) and was purified by chromatography eluting with EtOAc in iso-hexane (0-60%) using an JSCO CombiFlashTM system to yield the title compound as brown crystals. [M + H) + 687.

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Abstract

La présente invention concerne des composés de formule (I) où R1, R2, Ar, p, R4 et R5 sont tels que définis dans la présente invention, lesdits composés pouvant être employés dans le traitement de pathologies répondant à des médiateurs du récepteur CXCR2. La présente invention concerne également des compositions pharmaceutiques incluant les composés et des procédés de synthèse des composés.
PCT/EP2009/066354 2008-12-05 2009-12-03 Cyclobutène-1,2-diones 3,4-disubstituées en tant qu'antagonistes de récepteur cxcr2 WO2010063802A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2012080457A1 (fr) 2010-12-17 2012-06-21 Boehringer Ingelheim International Gmbh Phénols à fonctionnalité sulfonamide substituée par un système de cycles bicyclique en tant que médicaments
US8288588B2 (en) 2008-08-04 2012-10-16 Novartis Ag Squaramide derivatives as CXCR2 antagonist
WO2013061004A1 (fr) * 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux composés di-substitués de la diamino-3,4-cyclobutène-3-dione-1,2 utiles dans le traitement de pathologies médiées par des chimiokines
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WO2016183097A1 (fr) * 2015-05-11 2016-11-17 Abide Therapeutics, Inc. Procédés de traitement de l'inflammation ou de la douleur neuropathique
US9809581B2 (en) 2015-11-19 2017-11-07 Chemocentryx, Inc. Inhibitors of CXCR2
US9834545B2 (en) 2015-11-19 2017-12-05 Chemocentryx, Inc. Modulators of chemokine receptors
WO2019036374A1 (fr) * 2017-08-14 2019-02-21 Allergan, Inc. 3-cyclobutène-1,2-diones 3,4-disubstituées et leur utilisation
WO2019099838A1 (fr) 2017-11-16 2019-05-23 Novartis Ag Polythérapies
US10463753B2 (en) 2016-02-19 2019-11-05 Lundbeck La Jolla Research Center, Inc. Radiolabeled monoacylglycerol lipase occupancy probe
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US10975065B2 (en) 2018-09-21 2021-04-13 Pfizer Inc. N-substituted-dioxocyclobutenylamino-3-hydroxy-picolinamides useful as CCR6 inhibitors
US11021453B2 (en) 2012-01-06 2021-06-01 Lundbeck La Jolla Research Center, Inc. Carbamate compounds and methods of making and using same
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US11207294B2 (en) 2018-01-08 2021-12-28 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2
WO2021260528A1 (fr) 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022029573A1 (fr) 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations
US11273159B2 (en) 2016-11-16 2022-03-15 H. Lundbeck A/S Pharmaceutical formulations
WO2022215011A1 (fr) 2021-04-07 2022-10-13 Novartis Ag UTILISATIONS D'ANTICORPS ANTI-TGFβ ET D'AUTRES AGENTS THÉRAPEUTIQUES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
WO2022243846A1 (fr) 2021-05-18 2022-11-24 Novartis Ag Polythérapies
US11702393B2 (en) 2020-04-21 2023-07-18 H. Lundbeck A/S Synthesis of a monoacylglycerol lipase inhibitor
US11993588B2 (en) 2021-09-08 2024-05-28 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083624A1 (fr) * 2001-04-16 2002-10-24 Schering Corporation Cyclobutene-1,2-diones a disubstitution en positions 3,4 utilisees comme ligands de recepteurs de la chimiokine cxc
US20040106794A1 (en) * 2001-04-16 2004-06-03 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
WO2005075447A1 (fr) * 2004-01-30 2005-08-18 Schering Corporation Polymorphes cristallins d'un ligand du recepteur des cxc-chimiokines
WO2006072354A1 (fr) * 2005-01-07 2006-07-13 Merck Patent Gmbh Derives d'acide quadratique
DE102005035742A1 (de) * 2005-07-29 2007-02-01 Merck Patent Gmbh Quadratsäurederivate II
WO2008005570A1 (fr) * 2006-07-07 2008-01-10 Schering Corporation Cyclobutène-1,2-diones 3,4-disubstituées utilisées comme ligands de récepteur de chimiokine cxc

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083624A1 (fr) * 2001-04-16 2002-10-24 Schering Corporation Cyclobutene-1,2-diones a disubstitution en positions 3,4 utilisees comme ligands de recepteurs de la chimiokine cxc
US20040106794A1 (en) * 2001-04-16 2004-06-03 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
WO2005075447A1 (fr) * 2004-01-30 2005-08-18 Schering Corporation Polymorphes cristallins d'un ligand du recepteur des cxc-chimiokines
WO2006072354A1 (fr) * 2005-01-07 2006-07-13 Merck Patent Gmbh Derives d'acide quadratique
DE102005035742A1 (de) * 2005-07-29 2007-02-01 Merck Patent Gmbh Quadratsäurederivate II
WO2008005570A1 (fr) * 2006-07-07 2008-01-10 Schering Corporation Cyclobutène-1,2-diones 3,4-disubstituées utilisées comme ligands de récepteur de chimiokine cxc

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LAI ET AL: "Synthesis and structure-activity relationships of new disubstituted phenyl-containing 3,4-diamino-3-cyclobutene-1,2-diones as CXCR2 receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 18, no. 6, 10 February 2008 (2008-02-10), pages 1864 - 1868, XP022526296, ISSN: 0960-894X *

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US8329754B2 (en) 2008-08-04 2012-12-11 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US9115087B2 (en) 2008-08-04 2015-08-25 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8722925B2 (en) 2008-08-04 2014-05-13 Novartis Ag Squaramide derivatives as CXCR2 antagonist
WO2012001076A1 (fr) * 2010-06-29 2012-01-05 Galderma Research & Development Utilisation de squaramide dans la prévention et/ou le traitement de la rosacée
JP2013533870A (ja) * 2010-06-29 2013-08-29 ガルデルマ・リサーチ・アンド・デヴェロップメント 酒さの予防および／または治療におけるスクワラミドの使用
US8648118B2 (en) 2010-12-17 2014-02-11 Boehringer Ingelheim International Gmbh Bicyclic ring system substituted amide functionalised phenols as medicaments
WO2012080457A1 (fr) 2010-12-17 2012-06-21 Boehringer Ingelheim International Gmbh Phénols à fonctionnalité sulfonamide substituée par un système de cycles bicyclique en tant que médicaments
JP2013545790A (ja) * 2010-12-17 2013-12-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 医薬としての二環系置換スルホンアミド官能化フェノール
US8648070B2 (en) 2010-12-17 2014-02-11 Boehringer Ingelheim International Gmbh Bicyclic ring system substituted sulfonamide functionalised phenols as medicaments
US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
CN103958505A (zh) * 2011-10-28 2014-07-30 高德美研究及发展公司 用于治疗趋化因子介导的病理的二取代的3,4-二氨基-3-环丁烯-1,2-二酮化合物
US9388149B2 (en) 2011-10-28 2016-07-12 Galderma Research & Development Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
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FR2981934A1 (fr) * 2011-10-28 2013-05-03 Galderma Res & Dev Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
JP2014530894A (ja) * 2011-10-28 2014-11-20 ガルデルマ・リサーチ・アンド・デヴェロップメント ケモカイン媒介性疾患の処置に使用するための新規二置換３，４−ジアミノ−３−シクロブテン−１，２−ジオン化合物
JP2014530895A (ja) * 2011-10-28 2014-11-20 ガルデルマ・リサーチ・アンド・デヴェロップメント ケモカイン媒介性病変の処置に使用するための二置換３，４−ジアミノ−３−シクロブテン−１，２−ジオン化合物
WO2013061005A1 (fr) * 2011-10-28 2013-05-02 Galderma Research & Development Composés di-substitués de la diamino-3,4-cyclobutène-3-dione-1,2 utiles dans le traitement de pathologies médiées par des chimiokines
US9090596B2 (en) 2011-10-28 2015-07-28 Galderma Research & Development Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated pathologies
WO2013061004A1 (fr) * 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux composés di-substitués de la diamino-3,4-cyclobutène-3-dione-1,2 utiles dans le traitement de pathologies médiées par des chimiokines
FR2981935A1 (fr) * 2011-10-28 2013-05-03 Galderma Res & Dev Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
CN103958505B (zh) * 2011-10-28 2016-08-24 高德美研究及发展公司 用于治疗趋化因子介导的病理的二取代的3,4-二氨基-3-环丁烯-1,2-二酮化合物
CN103906738B (zh) * 2011-10-28 2016-09-07 高德美研究及发展公司 用于治疗趋化因子介导的疾病的新的二取代的3,4-二氨基-3-环丁烯-1,2-二酮化合物
US9580412B2 (en) 2011-10-28 2017-02-28 Galderma Research & Development Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases
US9526732B2 (en) 2011-10-28 2016-12-27 Galderma Research & Development Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated pathologies
US11530189B2 (en) 2012-01-06 2022-12-20 H. Lundbecka/S Carbamate compounds and methods of making and using same
US11021453B2 (en) 2012-01-06 2021-06-01 Lundbeck La Jolla Research Center, Inc. Carbamate compounds and methods of making and using same
WO2016183097A1 (fr) * 2015-05-11 2016-11-17 Abide Therapeutics, Inc. Procédés de traitement de l'inflammation ou de la douleur neuropathique
US11034674B2 (en) 2015-05-11 2021-06-15 H. Lundbeck A/S Methods of treating inflammation or neuropathic pain
US10450302B2 (en) 2015-05-11 2019-10-22 Lundbeck La Jolla Research Center, Inc. Methods of treating inflammation or neuropathic pain
US10370363B2 (en) 2015-11-19 2019-08-06 Chemocentryx, Inc. Inhibitors of CXCR2
US10988464B2 (en) 2015-11-19 2021-04-27 Chemocentryx, Inc. Modulators of chemokine receptors
US11945805B2 (en) 2015-11-19 2024-04-02 Chemocentryx, Inc Inhibitors of CXCR2
US11820759B2 (en) 2015-11-19 2023-11-21 Chemocentryx, Inc. Modulators of chemokine receptors
US9809581B2 (en) 2015-11-19 2017-11-07 Chemocentryx, Inc. Inhibitors of CXCR2
US10336736B2 (en) 2015-11-19 2019-07-02 Chemocentryx, Inc. Modulators of chemokine receptors
US11040960B2 (en) 2015-11-19 2021-06-22 Chemocentryx, Inc. Inhibitors of CXCR2
US9834545B2 (en) 2015-11-19 2017-12-05 Chemocentryx, Inc. Modulators of chemokine receptors
US10463753B2 (en) 2016-02-19 2019-11-05 Lundbeck La Jolla Research Center, Inc. Radiolabeled monoacylglycerol lipase occupancy probe
US11273159B2 (en) 2016-11-16 2022-03-15 H. Lundbeck A/S Pharmaceutical formulations
US11142517B2 (en) 2016-11-16 2021-10-12 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor
JP2020530848A (ja) * 2017-08-14 2020-10-29 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ３，４−二置換３−シクロブテン−１，２−ジオンおよびその使用
WO2019036374A1 (fr) * 2017-08-14 2019-02-21 Allergan, Inc. 3-cyclobutène-1,2-diones 3,4-disubstituées et leur utilisation
US11208377B2 (en) 2017-08-14 2021-12-28 Allergan, Inc. 3,4-disubstituted 3-cyclobutene-1,2-diones and use thereof
CN111225900A (zh) * 2017-08-14 2020-06-02 阿勒根公司 3,4-二取代的3-环丁烯-1,2-二酮及其用途
WO2019099838A1 (fr) 2017-11-16 2019-05-23 Novartis Ag Polythérapies
US11207294B2 (en) 2018-01-08 2021-12-28 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2
US11684606B2 (en) 2018-01-08 2023-06-27 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2
WO2020012337A1 (fr) 2018-07-10 2020-01-16 Novartis Ag Dérivés de 3-(5-amino-1-oxoisoindoline-2-yl)pipéridine-2,6-dione et leur utilisation dans le traitement de maladies dépendant des doigts de zinc 2 de la famille ikaros (ikzf2)
US10975065B2 (en) 2018-09-21 2021-04-13 Pfizer Inc. N-substituted-dioxocyclobutenylamino-3-hydroxy-picolinamides useful as CCR6 inhibitors
US11708360B2 (en) 2018-09-21 2023-07-25 Pfizer Inc. N-substituted-dioxocyclobutenylamino-3-hydroxy-picolinamides useful as CCR6 inhibitors
WO2020128972A1 (fr) 2018-12-20 2020-06-25 Novartis Ag Schéma posologique et combinaison pharmaceutique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2020165833A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxo-5-(pipéridin-4-yl)isoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2020165834A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxoisoindoline-2-yl)pipéridine-2,6-dione substitués et leurs utilisations
WO2021104506A1 (fr) * 2019-11-28 2021-06-03 中国医学科学院药物研究所 Composé sulfone cyclique et son procédé de préparation, composition pharmaceutique de celui-ci et son utilisation
WO2021123996A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Utilisations d'anticorps anti-tgf-bêtas et inhibiteurs de point de contrôle pour le traitement des maladies prolifératives
US11702393B2 (en) 2020-04-21 2023-07-18 H. Lundbeck A/S Synthesis of a monoacylglycerol lipase inhibitor
WO2021260528A1 (fr) 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022029573A1 (fr) 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations
WO2022215011A1 (fr) 2021-04-07 2022-10-13 Novartis Ag UTILISATIONS D'ANTICORPS ANTI-TGFβ ET D'AUTRES AGENTS THÉRAPEUTIQUES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
WO2022243846A1 (fr) 2021-05-18 2022-11-24 Novartis Ag Polythérapies
US11993588B2 (en) 2021-09-08 2024-05-28 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor

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